Alkyl-substituted-hexyl ethyl



Patented Apr. 2, 1935 r it ALKYL-SUBSTITUTED-HEXYL ETHYL I BARBIITIURIC ACID Horace A. Slionle, Indianapolis, Ind., assignor to Eli Lilly and Company, Indianapolis, Ind., a I corporation of Indiana No Drawing. Application February 26, 1934,

Serial No. 713,020

8 Claims. (Cl. 26033) It is the main object ofmy invention to' produce ethyl esters, which are represented by the followcertain 5,5-di-aliphatic-substituted barbituric ing formula: I acids, and their salts, in which one substituent'is 1 RI d the ethyl group, and the other substituent is a I i I I I I I 5 saturated branched-chain primary aliphatic radi- C H r I 5 cal having a straight chain containing 6 carbon I 0 atoms with an ethyl substituent on the number 2 I g d carbon atom, and if desired with a methyl sub- 1 I f stituent on one of the numbers 3, 4, and 5 carbon inwhich R a t samesignificance as before; 10 atoms- The Fecond Substituent may thus be any and R represents an alkyl radical having not to 10 0f h ll wm i I exceed 3 carbon atomanamely the methyl, ethyl. 2 ethy1 hexy1 and propyl radicals, and preferably the ethyl radical: Because of this preference, in making these I substituted malonic esters I prefer to work with 5 CHT-CHK-CHPCHr-EIPCHP the 'di-ethyl malon'ates1and so whenever I refer to "a malonic. ester, substituted or unsubstituted, 2 ethyl 3 methyl hexyl I mean the di-ethyl malonate unless otherwise 111i gem indicated. 7 II v I a In describing the various examples illustrative OH OH CH CH H CH F rof my invention, Ishall describe first themalonic 20 c. 2-ethyl-4-methy1-heXy1 I Q esters,'then-the=barbituric acids, and thenth cm 0 H barbiturates; and the procedures for respectively I 5 I l producing them. I CHa-CHg-CH-CH H-CHz- I Ma onicesters 25 d. 2-ethyl-5-methyl-hexyl V I CH O H In making the respective malonic esters, I use I13 5 5 saturated branched-chain primary aliphatic al- Q EPCHrCHwa I cohols having a straight chain containing 6 carbon atoms with an'ethyl substituent on the num- 30 An incidental object of my invention is to produce certain new intermediates. These are dialiphatic-substituted malonic esters.

The new 5,5-di-aliphatic-substituted barbituric her 2 carbonatom, and if desired with a methyl substituent on one of the numbers 3, 4, and 5 carbon atoms. These include the following:

acids and their salts which are included in this Letlwbhexanold 35 present application all have hypnotic act1on. 2I ethy1 3 methy1 hexano1 1 They are all represented by the following for- I r mula' l d. 2-ethyl-5-methy1-hexanol-1 R R R 01H; 40 ';H 64 Alcohol a is a commercially available product. 4

Alcoholsb, c,- and d may; be-prepared according (1) Y I I to the method describedby Connor and Adkins,

Y 0:115 CQN I I Journalihmerican Chemical Society, volume-54,

pages 4678 -4690jfor the year-1932' This article specifically describes alcoholsb and d on pages 45 in which R in at least two of the three places I 4681 and 4689; and while-it does not describe alrepresents hydrogen and in the third place repre-f cohol c, that alcohol can b e made by the same sents either hydrogen or a methyl group; procedure.

and X represents either hydrogen (if the com- In using these alcohols to make the malonic pound is an acid), or (if the compound is a salt). esters, I proceed as' followsz 50 either an alkali metal, suchas sodium, or ammo- .FirstI obtain thecorresponding bromide from nium, or a monoor di-alkyl ammonium radical, the alcohol. This may be done in any of the such as NH3-CH3 or -NH2(C2I-I5) 2. knownways, as-by treatingtherespective alco- These new acids and salts are prepared from hol with PBrs, with aqueous I-IBr, or with an-' I certain new di-substituted malonic esters, usually hydrous gaseous HBr.- I 5 Examples of the bromides thus obtained are the following:

l-bromo-2-ethyl-hexane 1-bromo-2-ethyl-3-methyl-hexane 1-bromo-2-ethyl-5-methyl-hexane These are purified by fractional distillation. The fractions which I used for the further synthesis were those which at 20 C. had refractive indexes of 1.4537 to 1.4547, 1.4611 1.4552 to 1.4557, respectively.

The respective malonic esters are prepared Y from these bromides. One mole, of sodium is dissolved in from 10 to 12 times its weight of abscelute alcohol, under a reflux condenser. One mole of ethyl malonic ester (ethyl di-ethyl-malonatel is then added. Desirably most of the alcohol that was used to dissolve the sodium is then removed, as by vacuum distillation. Then about, 1.1 moles of the respective bromide, produced as above described, is gradually added. The mixtureis refluxed for some hours, until it nolonger shows an alkaline reaction to moist litmus paper. Most of the alcohol remaining, whether or not 0 some had previously been removed, is" now re-- moved by vacuum distillation, leaving an oily residue Water isv added to this residue to dissolve out the sodium bromide present in it; and the oily layer, which is the. desired di-substituted malonic ester, is separated and dried. This disubstituted malonic ester is purified by fractional distillation in vacuo. When so purifiedit is a colorlessor pale yellow liquid in all the cases named. 1

The malonic esters which are obtained from the bromides given above as examples are the following:

Z-ethyZ-hemyl ethyl malonic ester This has a boiling pointof about1287-129" c'., at about 3.5 mm. pressure; and'is represented by. the following'formula: I v

2-ethyZ-3-methyl-h eaiyl ethyl mdlonic ester This has... boiling point of about -123 0.,

at about 2.5 mm. pressure; and is represented by the following formula:

2 -ethyl- -5-methyl -7temy l ethyl; malonic ester This has a boiling point bf about 146? t? substituted barbituric acids is as follows:

These barbituric acids are represented by the following general formula:

; in which R has the same significance as before.

In general, the method of preparing such di- Three moles of sodium are dissolved in 10 to 12 times its weight of absolute alcohol under a reflux condenser. To this are added about 1.6 moles of urea and 1 mole of .the di-substituted malonic ester of which the corresponding barbituric acid is desired.1.The mixture is gently refluxed for 12 to 15 hours, after which most of the.alcohol is removed by vacuum distillation. The residue is dissolved in water, and a sufficient amount of adilute acid, such as hydrochloric acid,is added to completely throw out of solution the di-substituted barbituric acid whichvhas been formed. This di-substituted barbituric acid comes out of solution in some cases as a solid, and in somev cases as'an oily liquid which solidifies on standing. .The di-substituted barbituric acid so obtained is separated, as by filtration; is then dried,

and washed with gasoline; and is then purified by recrystallization froindilute alcohol. The bar-. bituric acids thus obtained are allwhite crystalline solids; are insoluble in water, :and readily soluble in alcohol and ether; are bitter-tasting; and have hypnotic action.

The di-substituted barbituric acids which are obtained from the malonic esters given as examples are the following: V

Z-ethyZ-hemyl ethyl barbiturz'c acid This has a melting point; a'fter several recrystallizations from diluteralcohoLof 116'1l7 C.

It is represented by the following formula:

This has a melting point. after several recrys tallizations from dilute alcohol, of 151-1 54"C.

It is represented by the following formula: CH3 02H; a

"on on on 03- H-oH -OO-NH rut-r oo 2-ethyl -5-methyZ-hemyl eti t'yl barbittlficccz'd This has a melting point, after several recrystallizations from dilute alcohol, of 134-136 C. It is represented by the following formula:

CH3 CzHs co C2136 CONH M.

The temperaturesgiven were all obtained with a short-stem Anschiitz thermometer.

,BliiiBIrUiiArEs 7 All the above-described barbituric acids are soluble in solutions of alkali-metal hydroxides and ethylates, to form the corresponding alkali metal barbiturates in solution. The solid 'salts' may be obtained from such solutions. p

The new di-aliphatic-substituted barbiturates, which may all be represented by Formula 1 with X representing a metal or ammonium or a monoor di-alkyl ammonium radical, can perhaps best be prepared from the corresponding di-aliphaticsubstituted barbituric acids, as by reaction in a suitable solvent with either the hydroxide or the ethyla-te of the desired inorganic base, or with- For ammonia, or with the desired alkyliainine. instance:

A. Alkali-metal salts-The sodium salts of these di-substituted barbituric acids are all represented by the following general formula:

in which R. has the same significance as before. The other alkali-metal salts have the same general formula, except for the substitution of the other metal for sodium. These salts are prepared as follows:

A solution of one molar proportion of the hydroxide or the ethylate of the alkali metal, such as sodium, is added to a suspension or solution in a suitable solvent (such as alcohol) of one molar proportion of any of the herein-contemplated 5,5-di-aliphatic-substituted barbituric acids; which produces the desired barbiturate in solution. The amount of solvent used is desirably sufiicient to dissolve the salt thus produced. The solution is filtered; and is then evaporated, preferably under vacuum at a low temperature, until the salt is obtained in solid form.

The sodium salts of the di-substituted barbituric acids given as examples are the following:

Sodium 2-ethyl-hexyl ethyl barbiturate, which has the following formula:

CHrCHrCHrCHrCH-CHa CONH /C\ /CO OiHs CON Sodium 2-ethyl-3-methyl-hexyl ethyl barbiturate, which has the following formula:

Sodium 2-ethyl-5-methyl-hexyl ethyl barbiturate, which has the following formula:

These sodium salts are all white solids, soluble in water and alcohol, and insoluble in ether. They are all bitter-tasting, and their aqueous solutio'ns are alkalinein reaction. They-all have hypnotic properties, on both oralandparenteral administration. When these salts are desired in stable form sufiiciently free from contaminants so that clear water solutionsthereof suitable for intravenous injection may be obtained,"they'may be soobtained by, the method set forth in my Patent No. 1,856,792, granted May 3, 1932;

B. Ammonium and aZkyZ-amine sulfa-One molar proportion of any of the above de c ribed 5,5-di-aliphatic substitritdbarbituric Y acids' is dissolved in or addedto somewhat more than a I molar proportion of an aqueous oralcoholic solutionof concentrated ammonia or of the alkyl amine, suchfor instance as monoor di-methyl amine or monoor di-ethyl amine. The amount of liquid used should be sufficient to ensure complete reaction. The resultingbarbiturate crystallizes out or is concentrated to solid form. The formulas of these barbiturates correspond ingeneral to Formulas 11 to -l3 inclusive, save that NE;

is substituted forNa in the case'- of theammonium salts, or the pr'oper'alkyl-ammonium radical, 'such for instance as the methyl-ammonium radical (-NHa-CH3) is substituted for Na in the case of the alkyl-amine salts The above-described di-aliphatic-substituted barbituric acids and their salts are all of value as sedatives and hypnotics- I claim as my invention:

1. A barbituric compound which is represented by the following formula:

R R CaH; t t

om-cnu-cn- H-oH, co-NH C Ha in which R in at least two of the three places represents hydrogen'and in the third place represents either hydrogen or a methyl group; and

X represents either hydrogen, an alkali metal, ammonium, or a monoor di-alkyl ammonium 3. A 2-ethyl-hexyl ethyl barbituric compound which is represented by the following formula:

' OHl I OHa-CHr-CHr-CHz-Jlll-OH2 CO-NH o o N/ in which X represents either hydrogen, an alkali metal, ammonium, or a monoor di-alkyl ammonium radical.

4. Z-ethyl-hexyl ethyl barbituric acid, which is represented by the following formula:

02115 I omon,-om-on,-on-cm CO-NH 5. A 2-ethyl-3-methy1-hexyl, ethyl bvarbituric'. compound which is represented by the following formula: V a I in which X represents either hydrogen, an alkali metal, ammonium, 011a monoor di-alkyl ammonium radical.- t

6. 2-ethy1-3-methy1-hexy1 ethyl barbituric' acid, which is represented by the following formula: 1

1 a r fg ghm CH-OH -03 nice-0H "00- v.

o 00 CIHI/ C0--I|-I in which X represents either hydrogen, an alkali metal, .ammonium or a monoor di-alkvl ammonium radical.

8.,2-ethy1-5-methy1-hexy1 ethyl barbituric acid, which is represented by the following formula;

CH1 CaHr C CO HORACE A. SHONLE.

compoundwhich is represented by the f0110wing- 

